Glucuronidation: driving factors and their impact on glucuronide disposition

Glucuronidation is a well-recognized phase II metabolic pathway for a variety of chemicals including drugs and endogenous substances. Although it is usually the secondary metabolic pathway for a compound preceded by phase I hydroxylation, glucuronidation alone could serve as the dominant metabolic pathway for many compounds, including some with high aqueous solubility. Glucuronidation involves the metabolism of parent compound by UDP-glucuronosyltransferases (UGTs) into hydrophilic and negatively charged glucuronides that cannot exit the cell without the aid of efflux transporters. Therefore, elimination of parent compound via glucuronidation in a metabolic active cell is controlled by two driving forces: the formation of glucuronides by UGT enzymes and the (polarized) excretion of these glucuronides by efflux transporters located on the cell surfaces in various drug disposition organs. Contrary to the common assumption that the glucuronides reaching the systemic circulation were destined for urinary excretion, recent evidences suggest that hepatocytes are capable of highly efficient biliary clearance of the gut-generated glucuronides. Furthermore, the biliary- and enteric-eliminated glucuronides participate into recycling schemes involving intestinal microbes, which often prolong their local and systemic exposure, albeit at low systemic concentrations. Taken together, these recent research advances indicate that although UGT determines the rate and extent of glucuronide generation, the efflux and uptake transporters determine the distribution of these glucuronides into blood and then to various organs for elimination. Recycling schemes impact the apparent plasma half-life of parent compounds and their glucuronides that reach intestinal lumen, in addition to prolonging their gut and colon exposure.     

Alternative drug delivery approaches for the therapy of inflammatory bowel disease

This article shall give an overview on drug delivery systems for new therapeutic strategies in the treatment of inflammatory bowel disease. The various features of the different approaches allowing locally restricted drug delivery to the inflamed colon are discussed including the main physiological and pathophysiological limitations for the different systems. Conventional drug delivery systems are tightly adapted from developments for colonic delivery by oral administration triggered by release mechanisms owing to the physiological environment that these systems encounter in the colonic region. The newer developments in this context aim for an increased selectivity of drug delivery by targeting mechanisms which have a closer relation to pathophysiological particularities of the disease. Therefore, we were focused especially on new strategies for such treatment including liposomal formulations, cyclodextrins, micro- or nanoparticles, viral gene therapy approaches, and others. Effective and selective delivery even of an otherwise nonspecifically acting drug could provide new therapeutic pathways in the treatment of inflammatory bowel disease.     

Multiparticulate systems in the treatment of inflammatory bowel disease

This article shall give an overview on drug delivery systems under development for new therapeutic strategies in the treatment of inflammatory bowel disease. Local delivery of drugs in the colon is mainly aimed to improve efficacy to side-effect profiles. The various features of the different approaches allowing drug delivery to the inflamed colon are discussed including the main physiological and pathophysiological problems for different systems. Developments for colonic delivery by oral administration always tried to adapt the carriers to the physiological requirements which shall further increase the therapeutic efficiency and improve patient compliance. The newer carriers described here shall allow to exclude certain variations by physiological factors like local pH, transit throughout the gastrointestinal tract, the potential role of gut microflora, and drug dissolution in the diseased large intestine, which always have been impeding conventional carrier systems for this treatment. Therefore, especially new strategies for such treatment will be presented including liposomal formulations, nanoparticles, bacterial cytokine expression and viral gene therapy approaches. Effective and selective delivery even of an otherwise non-specifically acting drug could provide new therapeutic pathways in the treatment of inflammatory bowel disease.     

Efflux transporters and their clinical relevance

It is increasingly recognized that efflux transporters play an important role, not only in chemo protection e.g. multi-drug resistance, but also in the absorption, distribution, and elimination of drugs. The modulation of drug transporters through inhibition or induction can lead to significant drug-drug interactions by affecting intestinal absorption, renal secretion, and biliary excretion, thereby changing the systemic or target tissue exposure of the drug. Few clinically significant drug interactions that affect efficacy and safety are due to a single mechanism and there is considerable overlap of substrates, inhibitors, and inducers of efflux transporters and drug metabolizing enzymes, such as CYP3A. As well, genetic polymorphisms of efflux transporters have been correlated with human disease and variability of drug exposure. Accordingly, this review will discuss drug interactions and suitable probe substrates, as well as, the clinical relevance of the variability and modulation of efflux transporters and the exploitation of substrates as diagnostic tools. An update is given on inhibitors, which clinically reverse drug resistance and minimize the risk of metabolic interactions.     

Azo chemistry and its potential for colonic delivery

Improved delivery systems are needed for drugs currently in use to treat localized diseases of the colon. One promising approach is to deliver the drugs specifically to the colon, an approach that has gained importance recently in the treatment of these diseases. The advantages of targeting drugs specifically to the diseased colon include fewer systemic side effects, a need for lower doses of drugs, and maintenance of the drug in its intact form close to the target site. The potential for colon-specific delivery of therapeutic proteins and peptides is also of interest. To achieve colon-specific drug delivery following oral administration, the drug needs to be protected from absorption by the upper gastrointestinal tract and from degradation by the upper gastrointestinal tract environment, allowing the drug to be abruptly released into the proximal colon. One strategy for targeting orally administered drugs to the colon exploits carriers that are degraded specifically by colonic bacteria and utilizes microbially degradable polymers/drugs, especially azo-cross-linked polymers/drugs. Prodrugs utilizing azo linkages are sulfasalazine, ipsalazine, balsalazine, and olsalazine. These were developed for delivery of 5-amino salicylic acid to the colon for localized chemotherapy of inflammatory bowl disease. The azo-conjugation approach utilizes the ability of the colonic environment to cleave these conjugates and protects the drug from absorption or degradation in the upper gastrointestinal tract. It is believed that flavin mediators present in the colon and azo-reductase enzymes released from colonic bacteria are responsible for the degradation of azo-aromatic compounds for site-specific delivery of the drug to the colon.     

转运体介导的食物-药物相互作用

食物与药物之间的相互作用普遍存在,且作用机制也多种多样。目前,研究较多的是单个食物或食物中的某些营养成分通过调节药物转运体或代谢酶的功能从而影响药物的体内过程。食物对药物体内过程的影响包括吸收、分布、代谢、排泄四个方面,并且主要是调节其中参与的药物转运体和代谢酶的功能。转运体介导的食物对药物体内吸收的影响主要是通过调节肠上皮摄取型和外排型的转运体,从而影响药物的吸收;对分布的影响主要是通过调节体内一些屏障中的转运体;对代谢的影响主要是同时调节药物代谢酶和转运体;对排泄的影响是通过调节肾脏和肝脏胆汁排泄的药物转运体,从而影响药物的清除率。因此,转运体介导的食物与药物相互作用直接影响药物治疗的效果。     

Role of efflux pumps and metabolising enzymes in drug delivery

The impact of efflux pumps and metabolic enzymes on the therapeutic activity of various drugs has been well established. The presence of efflux pumps on various tissues and tumours has been shown to regulate the intracellular concentration needed to achieve therapeutic activity. The notable members of efflux proteins include P-glycoprotein, multi-drug resistance protein and breast cancer resistance protein. These efflux pumps play a pivotal role not only in extruding xenobiotics but also in maintaining the body’s homeostasis by their ubiquitous presence and ability to coordinate among themselves. In this review, the role of efflux pumps in drug delivery and the importance of their tissue distribution is discussed in detail. To improve pharmacokinetic parameters of substrates, various strategies that modulate the activity of efflux proteins are also described. Drug metabolising enzymes mainly include the cytochrome P450 family of enzymes. Extensive drug metabolism due to the this family of enzymes is the leading cause of therapeutic inactivity. Therefore, the role of metabolising enzymes in drug delivery and disposition is extensively discussed in this review. The synergistic relationship between metabolising enzymes and efflux proteins is also described in detail. In summary, this review emphasises the urgent need to make changes in drug discovery and drug delivery as efflux pumps and metabolising enzymes play an important role in drug delivery and disposition.     

Role of efflux pumps and metabolising enzymes in drug delivery

The impact of efflux pumps and metabolic enzymes on the therapeutic activity of various drugs has been well established. The presence of efflux pumps on various tissues and tumours has been shown to regulate the intracellular concentration needed to achieve therapeutic activity. The notable members of efflux proteins include P-glycoprotein, multi-drug resistance protein and breast cancer resistance protein. These efflux pumps play a pivotal role not only in extruding xenobiotics but also in maintaining the body's homeostasis by their ubiquitous presence and ability to coordinate among themselves. In this review, the role of efflux pumps in drug delivery and the importance of their tissue distribution is discussed in detail. To improve pharmacokinetic parameters of substrates, various strategies that modulate the activity of efflux proteins are also described. Drug metabolising enzymes mainly include the cytochrome P450 family of enzymes. Extensive drug metabolism due to the this family of enzymes is the leading cause of therapeutic inactivity. Therefore, the role of metabolising enzymes in drug delivery and disposition is extensively discussed in this review. The synergistic relationship between metabolising enzymes and efflux proteins is also described in detail. In summary, this review emphasises the urgent need to make changes in drug discovery and drug delivery as efflux pumps and metabolising enzymes play an important role in drug delivery and disposition.     

Pharmacokinetic interplay of phase II metabolism and transport: a theoretical study

Understanding of the interdependence of cytochrome P450 enzymes and P-glycoprotein in disposition of drugs (also termed "transport-metabolism interplay") has been significantly advanced in recent years. However, whether such "interplay" exists between phase II metabolic enzymes and efflux transporters remains largely unknown. The objective of this article is to explore the role of efflux transporters (acting on the phase II metabolites) in disposition of the parent drug in Caco-2 cells, liver, and intestine via simulations utilizing a catenary model (for Caco-2 system) and physiologically based pharmacokinetic (PBPK) models (for the liver and intestine). In all three models, "transport-metabolism interplay" (i.e., inhibition of metabolite efflux decreases the metabolism) can be observed only when futile recycling (or deconjugation) occurred. Futile recycling appeared to bridge the two processes (i.e., metabolite formation and excretion) and enable the interplay thereof. Without futile recycling, metabolite formation was independent on its downstream process excretion, thus impact of metabolite excretion on its formation was impossible. Moreover, in liver PBPK model with futile recycling, impact of biliary metabolite excretion on the exposure of parent drug [(systemic (reservoir) area under the concentration-time curve (AUC(R1))] was limited; a complete inhibition of efflux resulted in AUC(R1) increases of less than 1-fold only. In intestine PBPK model with futile recycling, even though a complete inhibition of efflux could result in large elevations (e.g., 3.5-6.0-fold) in AUC(R1), an incomplete inhibition of efflux (e.g., with a residual activity of ≥ 20% metabolic clearance) saw negligible increases (<0.9-fold) in AUC(R1). In conclusion, this study presented mechanistic observations of pharmacokinetic interplay between phase II enzymes and efflux transporters. Those studying such "interplay" are encouraged to adequately consider potential consequences of inhibition of efflux transporters in humans.     

Strategies for therapy of retinal diseases using systemic drug delivery: relevance of transporters at the blood-retinal barrier

INTRODUCTION: There is an increasing need for managing rapidly progressing retinal diseases because of the potential loss of vision. Although systemic drug administration is one possible route for treating retinal diseases, retinal transfer of therapeutic drugs from the circulating blood is strictly regulated by the blood-retinal barrier (BRB). AREAS COVERED: This review discusses the constraints and challenges of drug delivery to the retina. In addition, this article discusses the properties of drugs and the conditions of the BRB that affect drug permeability. The reader will gain insights into the strategies for developing therapeutic drugs that are able to cross the BRB for treating retinal diseases. Further, the reader will gain insights into the role of BRB physiology including barrier functions, and the effect of influx and efflux transporters on retinal drug delivery. EXPERT OPINION: When designing and selecting optimal drug candidates, it's important to consider the fact that they should be recognized by influx transporters and that efflux transporters at the BRB should be avoided. Although lipophilic cationic drugs are known to be transported to the brain across the blood-brain barrier, verapamil transport to the retina is substantially higher than to the brain. Therefore, lipophilic cationic drugs do have a great ability to increase influx transport across the BRB.     

Bacteria and pH-sensitive polysaccharide-polymer films for colon targeted delivery

The colon provides drug delivery opportunities for colon-specific and systemic delivery of various therapeutic agents. Different strategies have been utilized in targeting drugs to the colon. Recently, integrated systems which incorporate dual mechanisms in colon targeted delivery have received a lot of attention. Of particular interest is bacteria-aided biomaterials and pH-sensitive polymeric film (BPSF) coating for colon targeted drug delivery. The major constituents of these films are polysaccharides and pH-sensitive polymers. The pH-sensitive polymer retards drug release in the stomach and small intestine, while the polysaccharide is digested by colonic enzymes. Digestion of the polysaccharides by bacterial glycosidic enzymes increases the pore density in the film to facilitate drug release. Generally, bacteria-aided biomaterials and pH-sensitive films can be applied to the delivery of most small organic molecules to the colon. The review encompasses the pharmaceutical design parameters such as film digestibility, swelling index and dry mass loss (that provide molecular mechanistic analysis of film permeability) as well as tensile strength, elastic modulus, and elongation at break (that describe the desirable mechanical properties of the films). A critical analysis of formulation, techniques for characterization of film properties and drug-release kinetics from these systems are emphasized.     

Novel oral colon-specific drug delivery systems for pharmacotherapy of peptide and nonpeptide drugs

The increasing number of peptide and protein drugs being investigated demands the development of dosage forms which exhibit site-specific release. Delivery of drugs into systemic circulation through colonic absorption represents a novel mode of introducing peptide and protein drug molecules and drugs that are poorly absorbed from the upper gastrointestinal (GI) tract. Oral colon-specific drug delivery systems offer obvious advantages over parenteral administration. Colon targeting is naturally of value for the topical treatment of diseases of the colon such as Crohn's disease, ulcerative colitis and colorectal cancer. Sustained colonic release of drugs can be useful in the treatment of nocturnal asthma, angina and arthritis. Peptides, proteins, oligonucleotides and vaccines are the potential candidates of interest for colon-specific drug delivery. Sulfasalazine, ipsalazide and olsalazine have been developed as colon-specific delivery systems for the treatment of inflammatory bowel disease (IBD). The vast microflora and distinct enzymes present in the colon are being increasingly exploited to release drugs in the colon. Although the large intestine is a potential site for absorption of drugs, some difficulties are involved in the effective local delivery of drugs to the colon bypassing the stomach and small intestine. Furthermore, differential pH conditions and long transit time during the passage of drug formulations from mouth to colon create numerous technical difficulties in the safe delivery of drugs to the colon. However, recent developments in pharmaceutical technology, including coating drugs with pH-sensitive and bacterial degradable polymers, embedding in bacterial degradable matrices and designing into prodrugs, have provided renewed hope to effectively target drugs to the colon. The use of pH changes is analogous to the more common enteric coating and consists of employing a polymer with an appropriate pH solubility profile. The concept of using pH as a trigger to release a drug in the colon is based on the pH conditions that vary continuously down the GI tract. Polysaccharide and azopolymer coating, which is refractory in the stomach and small intestine yet degraded by the colonic bacteria, have been used as carriers for colon-specific targeting. Finally, the availability of optimal preclinical models and clinical methods fueled the rapid development and evaluation of colon-specific drug delivery systems for clinical use. Future studies may hopefully lead to further refinements in the technology of colon-specific drug delivery systems and improve the pharmacotherapy of peptide drugs.     

Strategies for therapy of retinal diseases using systemic drug delivery: relevance of transporters at the blood–retinal barrier

Introduction: There is an increasing need for managing rapidly progressing retinal diseases because of the potential loss of vision. Although systemic drug administration is one possible route for treating retinal diseases, retinal transfer of therapeutic drugs from the circulating blood is strictly regulated by the blood–retinal barrier (BRB).

Areas covered: This review discusses the constraints and challenges of drug delivery to the retina. In addition, this article discusses the properties of drugs and the conditions of the BRB that affect drug permeability. The reader will gain insights into the strategies for developing therapeutic drugs that are able to cross the BRB for treating retinal diseases. Further, the reader will gain insights into the role of BRB physiology including barrier functions, and the effect of influx and efflux transporters on retinal drug delivery.

Expert opinion: When designing and selecting optimal drug candidates, it's important to consider the fact that they should be recognized by influx transporters and that efflux transporters at the BRB should be avoided. Although lipophilic cationic drugs are known to be transported to the brain across the blood–brain barrier, verapamil transport to the retina is substantially higher than to the brain. Therefore, lipophilic cationic drugs do have a great ability to increase influx transport across the BRB.     

Polymer colon drug delivery systems and their application to peptides, proteins, and nucleic acids

Most therapeutic peptides and proteins are administered via the parenteral route, which presents numerous drawbacks and limitations. To overcome these drawbacks, alternative administration routes, such as oral or mucosal routes, have been investigated. The oral route presents a series of attractive advantages for the administration of therapeutic compounds, such as the avoidance of the pain and discomfort associated with injections, good patient compliance, and being less expensive to produce. However, oral administration of peptides, proteins, or nucleic acids also presents several difficulties because of their instability in the upper gastrointestinal (GI) tract and their poor transport across biologic membranes. Among the various approaches developed to improve the oral delivery of peptides, proteins, or nucleic acids, specific delivery to the colon has attracted a lot of interest because of its potential for the local treatment of colonic diseases, systemic delivery of poorly absorbed drugs, and vaccine delivery. Numerous pharmaceutical approaches described in this review have been exploited for the development of colon-targeted drug delivery systems using various concepts, such as pH-dependent, time-dependent, pressure-controlled, or bacterially triggered delivery systems. The action of the pH-dependent delivery systems is based on pH differences between the stomach and the ileum. Time-dependent delivery systems are based on the transit time of pharmaceutical dosage forms in the GI tract, drug release being delayed until they reach the colon. A combination of pH- and time-dependent delivery systems has also been described to avoid the drawbacks of both strategies. The pressure-controlled delivery concept exploits the physiologic luminal pressure of the colon as the driving force for site-specific delivery of drugs. Finally, bacterially triggered delivery systems exploit the enormous diversity of enzymatic activity associated with the colonic microflora. Bacterially triggered delivery systems are generally composed of polymers, which are specifically degraded by colonic enzymes of microbial origin. These polymers have been used to form prodrugs with the drug moiety, as coating materials for the drug core, or as embedding media to entrap the drug into matrix or hydrogel systems. Each of these concepts has advantages and limitations. They present varied colonic specificity and, among them, bacterially triggered delivery systems in particular show the greatest potential for colonic delivery of peptides, proteins, and nucleic acids.     

Polymeric efflux pump inhibitors in oral drug delivery

Drug efflux pump transporters of the ATP-binding cassette family such as P-glycoprotein and multidrug resistance proteins 1 and 2 are believed to confer multidrug resistance to tumor cells and affect overall absorption, distribution, metabolism, and elimination of orally administered clinically important therapeutic substances. By inhibiting these efflux transporters, an extrusion of the drugs back into the lumen can be diminished and consequently systemic exposure to orally administered drugs can be significantly improved. A number of compounds have been described which inhibit functioning of efflux pump transporters. Apart from the low-molecular-mass efflux pump inhibitors frequently undergoing interactions with co-administered drugs and leading to systemic adverse effects, various polymers have been recently found to exert an inhibitory effect. Because of their high molecular mass, polymeric efflux pump inhibitors offer the advantage of not being absorbed from the gastrointestinal tract and subsequently systemic toxic adverse effects can be excluded. Results of various in vitro and in vivo studies confirmed the efficacy of polymers as efflux pump inhibitors in oral drug delivery. The use of polyoxylates, pluronic block copolymers, dendrimers, polysaccharides, and thiolated polymers in formulations for oral drug delivery appears to be a promising strategy. This review summarizes the recent results in this field.     

Coupling of conjugating enzymes and efflux transporters: impact on bioavailability and drug interactions

Abstract: Conjugating enzymes are traditionally recognized as one of the major biological barriers to the entry of xenobiotics/drugs into systemic circulation and represent one of the main pathways for their elimination. Similar to drugs that undergo extensive phase I metabolism, drugs that undergo extensive conjugation have poor bioavailability and are more prone to metabolism-based drug interactions. Previously, enterohepatic recycling is used to explain why certain xenobiotics have half-lives that are much longer than expected from intravenous injection studies. In addition, changes in expression levels of metabolic enzymes due to chemical induction or suppression are often recognized as the source of drug interaction or toxicity of pollutants and carcinogens. These traditional approaches, whereas yielding highly valuable information, fail to recognize the fact that many conjugates (especially hydrophilic ones) cannot permeate the cell membrane.In the present review, we will focus on the coupling process that involves both conjugating enzymes and efflux transporters. We will briefly review conjugating enzymes capable of producing highly hydrophilic metabolic products. The other focus of this review is on various transporters capable of moving negatively charged hydrophilic conjugates across the cellular membrane. Evidence will support the hypothesis that efficient coupling of the conjugating enzymes and efflux transporters enables enterohepatic recycling and enteric recycling processes. Termed as a "revolving door" theory, the hypothesis focuses on the role played by efflux transporter capable of modulating the cellular excretion of hydrophilic metabolites. Coupling process in intestine, liver and kidney will be discussed with an emphasis on the intestinal coupling process, since we have just begun to understand it. Biological consequence and new insights into how coupling process can impact bioavailability of xenobiotics, biological functions of drugs and carcinogens, and drug interactions will be discussed.     

Nuclear receptors in the multidrug resistance through the regulation of drug-metabolizing enzymes and drug transporters

Chemotherapy is one of the three most common treatment modalities for cancer. However, its efficacy is limited by multidrug resistant cancer cells. Drug metabolizing enzymes (DMEs) and efflux transporters promote the metabolism, elimination, and detoxification of chemotherapeutic agents. Consequently, elevated levels of DMEs and efflux transporters reduce the therapeutic effectiveness of chemotherapeutics and, often, lead to treatment failure. Nuclear receptors, especially pregnane X receptor (PXR, NR1I2) and constitutive androstane activated receptor (CAR, NR1I3), are increasingly recognized for their role in xenobiotic metabolism and clearance as well as their role in the development of multidrug resistance (MDR) during chemotherapy. Promiscuous xenobiotic receptors, including PXR and CAR, govern the inducible expressions of a broad spectrum of target genes that encode phase I DMEs, phase II DMEs, and efflux transporters. Recent studies conducted by a number of groups, including ours, have revealed that PXR and CAR play pivotal roles in the development of MDR in various human carcinomas, including prostate, colon, ovarian, and esophageal squamous cell carcinomas. Accordingly, PXR/CAR expression levels and/or activation statuses may predict prognosis and identify the risk of drug resistance in patients subjected to chemotherapy. Further, PXR/CAR antagonists, when used in combination with existing chemotherapeutics that activate PXR/CAR, are feasible and promising options that could be utilized to overcome or, at least, attenuate MDR in cancer cells.     

Exploiting microspheres as a therapeutic proficient doer for colon delivery: a review

Introduction: Colon-specific drug delivery systems have recently gained importance for delivering a variety of therapeutic agents via oral route. This mode offers the feasibility of treating colonic pathologies with less risk of bioburden to other organs/tissues and has been widely researched for the delivery of challenging drugs. Microspheres targeted to colon have occupied central position on drug delivery due to their small size that offers characteristic intrinsic properties attributable to the carrier.

Areas covered: The present deliberation precariously covers the capacious usage of microspheres for the treatment of local colonic pathologies like colon carcinomas, inflammatory bowel disease and parasitic diseases using natural as well as synthetic carriers. The write up also encompasses clinical application of microspheres.

Expert opinion: Microspheres have comprehensive potential to be marketed as the patient-friendly formulation, as it would provide direct treatment at the disease site and, consequently, lower dosing and reducing systemic side effects. Wherefore, the major obstacles in delivering drugs to the colon like the absorption and degradation pathways in the proximal part of GIT could be easily overcome, and also a range of pathologies from constipation and diarrhea to the exhaustive inflammatory bowel diseases and colon carcinoma could be cured.     

Drug efflux pumps: challenges and opportunities. 14-18 November 1999, New Orleans, LA, USA

A symposium entitled 'Drug efflux pumps: challenges and opportunities' addressed the detection and functional characterization of drug efflux pumps, their influence on the cytochrome P450 (CYP450) system and their role in blood-brain barrier (BBB) permeability. Drug efflux pumps utilize ATP as the energy source in exporting solutes, and belong to the family of ATP-binding cassette transporters (ABC transporters). P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP) are members of this family of transporters. These transporters are overexpressed in cancer cells leading to decreased drug accumulation and hence drug resistance. Another causative factor for drug resistance is increased elimination mechanisms, metabolism by CYP450 enzymes being the most important. The multidrug resistance gene (mdr) is a key determinant in the expression of CYP3A enzymes, the most predominant subclass of CYP450. New techniques are being developed to identify and characterize drug efflux pumps, the latest being gamma-scintigraphy and hypertonic saline (HTS). Efflux pumps play a major role in restricting the drug transport across the BBB. Currently, structural domains that are responsible for the functional activity of the efflux proteins are being investigated to design better inhibitors for drug efflux pumps.     

Pharmacogenetics and immunosuppressor drugs: impact and clinical interest in transplantation

The domain of solid organ transplantation is characterized by the use of variable drug combinations with drug-drug interactions, and the presence of two genomes, that of the transplanted organ and that of the receiver, which can be involved in the pharmacogenetics of these drugs. This paper is a literature review of the impact of the genetic polymorphisms of the metabolic enzymes, efflux transporters and therapeutic targets of the main immunosuppressive drugs (cyclosporine, tacrolimus, sirolimus and mycophenolate) on the dose-concentration and concentration-effect relationships of these drugs. The polymorphisms of metabolic enzymes have significant effects on the pharmacokinetics of all these drugs, but the clinical trials for validating treatment individualization based on these genetic differences are still lacking. It should be noted that the influence of the donor's genome has seldom been studied and has been found to be significant in liver transplant recipients. The influence of efflux transporter genes polymorphisms, in particular of P-glycoprotein and MPR2, is controversial. As for the polymorphisms of the drug targets genes, either they have not been reported (calcineurin, mTOR), or their influence has only been the subject of a few preliminary studies (IMPDH2). The pharmacogenetics of immunosuppressants is thus still an open field for investigations and potential therapeutic progress.